A phase I trial of veliparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and topotecan (TPT) in patients with solid tumors.
Andrea E. Wahner HendricksonMichael E. MenefeeLynn C. HartmannHarry J. LongDonald W. NorthfeltJoel M. ReidFleix Boakye-AgyemanKaren S. FlattenGuy G. PoirierJanet L. LensingCharles ErlichmanScott H. KaufmannPaul Haluska
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TPS2618 Background: PARPs are a highly conserved family of enzymes whose predominant function is to preserve genomic integrity following DNA damage. Preclinical studies demonstrated that PARP inhibitors enhance the cytotoxicity of DNA damaging agents. Specifically, PARP inhibition sensitizes tumor cells to topotecan in vitro and in vivo by trapping PARP1 on damaged DNA and preventing repair of topo I-induced DNA damage (Patel et al., J. Biol. Chem. 287:4198, 2012). Veliparib has been combined with daily topotecan but found to be quite myelosuppressive, requiring reduction in doses of both agents (Kummar et al., Cancer Res. 71:5626, 2011). Based on these data, we sought to determine the maximum tolerated dose (MTD) of veliparib in combination with the less myelosuppressive weekly administration of topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells as well as the pharmacokinetics of both agents. Methods: Eligible patients include any histologically confirmed solid tumor malignancy that is metastatic or unresectable with measurable disease (longest diameter > 2 cm with conventional CT) in patients 18 or older who have received < 2 chemotherapy regimens, ECOG PS < 2 and adequate bone marrow, renal and hepatic function. Using a standard 3+3 design, patients have been treated with veliparib PO twice daily on days 1-3, 8-10 and 15-17 and topotecan IV on days 2, 9 and 16 every 28 days. The trial is currently enrolling at veliparib 300 mg PO twice daily and topotecan 3 mg/m2/dose. Once MTD is established, a phase II clinical trial in platinum resistant ovarian, peritoneal and fallopian tube malignancies is planned. Supported in part by UM1 CA186686 and P50 CA136393. Clinical trial information: NCT01012817 Clinical trial information: NCT01012817.Keywords:
Veliparib
Topotecan
PARP inhibitor
Olaparib
Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). This review provides an update on oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BC. Olaparib and talazoparib are PARP inhibitors approved as monotherapies for deleterious/suspected deleterious germline BRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for metastatic BC and in Europe for locally advanced/metastatic BC. Talazoparib is approved for locally advanced/metastatic BC in the USA and Europe. In phase 3 trials, olaparib and talazoparib monotherapies demonstrated significant progression-free survival benefits compared with chemotherapy. Common toxicities were effectively managed by supportive treatment and dose interruptions/reductions. Veliparib combined with platinum-based chemotherapy has also shown promise for locally advanced/metastatic BC in a phase 3 trial. Differences in efficacy and safety across PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) may relate to differences in potency of PARP trapping on DNA and cytotoxic specificity. PARP inhibitors are being investigated in early BC, in novel combinations, and in patients without germline BRCA mutations, including those with somatic BRCA mutations and other HRR gene mutations. Ongoing phase 2/3 studies include PARP inhibitors combined with immune checkpoint inhibitors for the treatment of triple-negative BC. Wider access to testing for BRCA and other mutations, and to genetic counseling, are required to identify patients who could benefit from PARP inhibitor therapy. The advent of PARP inhibitors has potential benefits for BC treatment beyond the locally advanced/metastatic setting.
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Abstract An inherited mutation in the BRCA1 gene leads to genomic instability and those with this mutation have a 50-80% risk for developing breast cancer by age 70. Though bilateral prophylactic mastectomy and surveillance are viable options for this high-risk population, chemoprevention may serve as a good alternative strategy. BRCA1 functions to repair double stranded DNA breaks via homologous recombination and as such, BRCA1 mutations force the cells to rely on other DNA repair mechanisms such as base excision repair, a process which requires Poly ADP ribose polymerase (PARP). Thus, PARP inhibition in BRCA1-deficient cells may induce apoptosis in these cells, which would otherwise develop into a tumor, while leaving normal cells intact. Olaparib and veliparib are promising PARP inhibitors that are currently in clinical trials for breast cancer treatment; however, their role in cancer prevention has not been examined. Hence, this study evaluated the effect of these PARP inhibitors in chemoprevention in the BrcaCo/Co;MMTV-Cre;p53+/- mouse model. Mice were fed continuously with olaparib (200 mg/kg diet) or veliparib (100 mg/kg diet) and tumor development was assessed. Both olaparib and veliparib significantly delayed tumor development by 6.5 and 2.4 weeks respectively (p<0.05) compared to their controls but olaparib was more effective than veliparib. To determine the lowest dose required for prevention, a dose de-escalation study was done and tumor development was assessed in mice fed with 100, 50, or 25 mg/kg of olaparib in diet. Tumor development was significantly delayed by 3.2 and 3.5 weeks (p<0.05) in mice fed with 50 and 100 mg/kg of olaparib diets respectively compared to their controls. To circumvent the possibility of drug resistance and adverse drug reaction from prolonged use of olaparib, an intermittent dosing regimen was examined where mice cycled through 200 mg/kg of olaparib diet for 2 weeks followed by a 4-week rest period of control diet. Intermittent treatment with olaparib significantly delayed tumor development by 5.7 weeks (p<0.05), which was almost as effective as continuous olaparib treatment. BrdU staining revealed that olaparib significantly reduced proliferation (p<0.05) when compared to their controls at both 24 (9.9% vs. 13.5% in hyperplastic areas; 4.5% vs. 9.5% in mammary ducts) and 30 weeks (9% vs. 15.9% in hyperplastic areas; 8.9% vs. 17.6% in mammary ducts) of age. A significant increase in apoptosis in hyperplastic areas from mice treated with olaparib compared to the control group (12.3% vs. 8.4%; p<0.05) was also observed by TUNEL staining at 30 weeks. Taken together, these studies demonstrated that olaparib is an effective agent that can be used intermittently to delay tumor development by reducing proliferation and inducing apoptosis in BRCA1-deficient mice. These results highlight the potential for using PARP inhibitors as novel preventive strategies to manage cancer risk in BRCA1 mutation carriers. Citation Format: Ciric To, Charlotte R. Williams, Darlene B. Royce, Ryan M. Collins, Michael B. Sporn, Karen T. Liby. Olaparib and veliparib as effective PARP inhibitors for cancer prevention in a BRCA1-deficient mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2965. doi:10.1158/1538-7445.AM2014-2965
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Abstract Among the clinical inhibitors of poly(ADP-ribose) polymerases (PARPs) and the commonly used PARP research tool compounds, veliparib and niraparib were recently identified as the most selective inhibitors of PARP1 and PARP2. We characterized the potency of A-966492, a PARP inhibitor with a chemical structure similar to veliparib and niraparib, in in vitro inhibition experiments of six PARP family enzymes. We find that the selectivity of A-966492 for PARP1 and PARP2 is intermediate between veliparib and niraparib.
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Currently, olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has been approved as maintenance therapy for patients with germline BRCA mutations and metastatic pancreatic cancer. However, platinum-based chemotherapy, which induces synthetic lethality with PARP inhibitor treatment, is still controversial. Hence, we aimed to examine a platinum-based drug in combination with a PARP inhibitor and generate data regarding the use of a PARP inhibitor in the overall treatment of pancreatic cancer.Using the Capan-1 cell line (BRCA2-mutant pancreatic cancer cell line), we evaluated the combinatorial effects of olaparib, a PARP inhibitor, and oxaliplatin by cell viability, combination index, western blotting, immunocytochemistry, flow cytometry, apoptosis assays and in vivo experiments.Capan-1 cells showed high sensitivity to olaparib due to the alteration in PARP activity, which led to cell death through the accumulation of oxaliplatin-induced DNA damage. Beyond DNA damage, oxaliplatin also suppressed the CDK1/BRCA1 signaling axis, which induced defects in homologous recombination repair. Additionally, inhibition of CDK1, a biomarker for oxaliplatin efficacy, induced cell death regardless of the BRCA mutation profile.Oxaliplatin may be used in combination with olaparib in PDAC patients with DNA damage repair mutations. Our findings highlight CDK1 as a potential therapeutic target for pancreatic cancer.
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TPS2618 Background: PARPs are a highly conserved family of enzymes whose predominant function is to preserve genomic integrity following DNA damage. Preclinical studies demonstrated that PARP inhibitors enhance the cytotoxicity of DNA damaging agents. Specifically, PARP inhibition sensitizes tumor cells to topotecan in vitro and in vivo by trapping PARP1 on damaged DNA and preventing repair of topo I-induced DNA damage (Patel et al., J. Biol. Chem. 287:4198, 2012). Veliparib has been combined with daily topotecan but found to be quite myelosuppressive, requiring reduction in doses of both agents (Kummar et al., Cancer Res. 71:5626, 2011). Based on these data, we sought to determine the maximum tolerated dose (MTD) of veliparib in combination with the less myelosuppressive weekly administration of topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells as well as the pharmacokinetics of both agents. Methods: Eligible patients include any histologically confirmed solid tumor malignancy that is metastatic or unresectable with measurable disease (longest diameter > 2 cm with conventional CT) in patients 18 or older who have received < 2 chemotherapy regimens, ECOG PS < 2 and adequate bone marrow, renal and hepatic function. Using a standard 3+3 design, patients have been treated with veliparib PO twice daily on days 1-3, 8-10 and 15-17 and topotecan IV on days 2, 9 and 16 every 28 days. The trial is currently enrolling at veliparib 300 mg PO twice daily and topotecan 3 mg/m2/dose. Once MTD is established, a phase II clinical trial in platinum resistant ovarian, peritoneal and fallopian tube malignancies is planned. Supported in part by UM1 CA186686 and P50 CA136393. Clinical trial information: NCT01012817 Clinical trial information: NCT01012817.
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Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy. Comparable to rucaparib development, other PARP inhibitors, such as olaparib, niraparib, veliparib and talazoparib, are developing CDx tests for targeted therapy. PARP inhibitor clinical trials and CDx assays are discussed in this review, as are potential PARP inhibitor combination therapies and likely resistance mechanisms.
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Abstract We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors act by a novel allosteric mechanism of action that involves the trapping of PARP-DNA complexes in addition to their previously established NAD-competitive catalytic inhibitory mechanism). We also demonstrated that PARP inhibitors differ in their ability to trap PARP-DNA complexes, with olaparib being more effective than veliparib in spite of their comparable potency as catalytic PARP inhibitors). Here, by using PARP knockout cells, olaparib and veliparib, we tested the role of PARP trapping in the potentiating effect of PARP inhibitors with the alkylating agent temozolomide and the topoisomerase I inhibitor, camptothecin. Using isogenic chicken DT40 cells, we show that PARP-dependent potentiation of temozolomide is markedly greater for olaparib than veliparib, and goes beyond knocking out PARP-1. On the other hand, in the case of camptothecin, knocking out PARP-1 has a greater effect than veliparib or olaparib. In human DU145 prostate cancer and SF295 glioblastoma cells, olaparib is markedly more potent than veliparib in potentiating the cytotoxicity of temozolomide whereas both olaparib and veliparib are almost comparable in the case of camptothecin. By measuring cellular PARP-DNA complexes), we find that in the case of temozolomide, olaparib is a least 10-fold more potent than veliparib at trapping PARP-DNA complexes. On the other hand, in the case of camptothecin, neither olaparib nor veliparib produced detectable trapping of PARP-DNA complexes. Finally, olaparib fails to sensitize DT40, DU145 or SF295 cells to cisplatin and does not induce detectable PARP-DNA complexes in cisplatin-treated cells. These results suggest that, in the case of temozolomide, olaparib trapping of PARP-DNA complexes is more toxic than inactivating PARP catalytic activity, which is not the case for topoisomerase I-induced DNA damage, where catalytic inactivation of PARP appears to be the sole enhancing mechanism. Citation Format: Yves G. Pommier, Junko Murai. Differential potentiation of temozolomide and camptothecin by the PARP inhibitors olaparib and veliparib in relationship with their PARP-DNA trapping abilities, and lack of impact of PARP inhibitors on cisplatin activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3421. doi:10.1158/1538-7445.AM2013-3421
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Abstract Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1Co/Co;MMTV-Cre;p53+/−) mouse model. In dose de-escalation studies, mice were fed with control, veliparib (100 mg/kg diet), or olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed with olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option. Cancer Prev Res; 7(7); 698–707. ©2014 AACR.
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